**21. Genetics of neonatal lupus**

Neonatal lupus erythematosus is noticed in the newborns of women suffering from SLE, and it is characterized by an erythematosus rash around the eyes similar to spectacles, a heart block and the presence of anti-Ro antibodies in the serum.

Neonatal lupus has been associated with the HLA-DRB102, HLA-DRB103 and the-308A allele linked to higher TNF- alpha production; these are present in the majority of children with this rash [42].

## **22. Chilblain lupus erythematosus and the TREX1 gene**

Chilblain lupus erythematosus is a rare subtype of chronic cutaneous lupus more frequently encountered in middle-aged women and can evolve into SLE in some cases. (18–20%) The clinical picture is characteristic of an acral distribution of bluish-red inflammatory skin lesions on upper and lower extremities following exposure to cold or damp weather. Rarely familial cases have been reported and are associated with autosomal dominant mutations in the TREX gene encoding the 3–5 DNA exonuclease. The TREX1 gene is located on chromosome 3p21. 0.5–3% of all patients with SLE carried mutations in TREX1 [43, 44].

## **23. Lupus and gender—X-linked genes associated with lupus**

Lupus erythematosus is a disease that affects nine (9) times more frequently females than males. Females have a stronger immune system than males; this can be explained by evolutionary biology. Women are destined to be pregnant and during pregnancy their immune system is suppressed to tolerate the existence and development of the fetus. Therefore, their immune system has to be more robust than that of males to compensate for this relative deficiency during gestation - this is the compensation theory. According to the Lyon theory, women have two chromosomes, but one copy is turned off in every cell very early in embryonic development; this process is known as X inactivation. Recent research, however, revealed that 15 per cent of the genes of the supposedly inactivated X chromosome are still turned on that the number of certain proteins produced in women is an increase compared with that in men. Particularly in women with lupus, some genes are active on both X copies and this higher activity correlates with disease severity [45]. Anguera M has also recently discovered that in mice mature immune cells undergo significant dynamic changes that could make it easier for X-linked genes to get turned on when they should be off.

### **24. The AIRE gene**

The AIRE gene was discovered in 1997 and plays an important role in autoimmune regulation. As it is expressed by cells in the thymus, it helps T cells to recognize if proteins presented to them are components of the self or non-self substances. It influences the expression of a wide variety of self-antigens in the thymus and is essential to the negative selection of self-reactive cells and the establishment of self-tolerance. The activity of AIRE is partially controlled by sex hormones, with estrogens and progesterone turning down the expression of AIRE while testosterone increasing its production. Under the influence of sex hormones, women at puberty make less AIRE than men, resulting in more self-reactive T cells escaping from the thymus and causing autoimmune disease. It has been discovered that the AIRE Ser196Ser synonymous variant is a risk factor for SLE.

*Lupus Genetics DOI: http://dx.doi.org/10.5772/intechopen.106372*

Another X-linked gene is the gene for toll-like receptor7 or TLR-7 that encodes a protein that recognizes pathogens and increases the production of interferons - molecules directly implicated in the pathogenesis of lupus. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus. Also, X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus [46, 47].

## **25. Epigenetic changes and SLE**

Epigenetic processes are molecular events that affect gene expression by reorganizing the structure of chromatin without altering the DNA sequence [48]. Such mechanisms include:


Epigenetic patterns can be modified by environmental factors or internal ones such as medicines administered to the patients. SLE is one of the disorders where epigenetics plays a major role in the development of the disease. Monozygotic twins that are equipped with the same genome for SLE susceptibility present less than 50% concordance rate. This implies that other mechanisms, mostly epigenetics, are implicated in the pathogenesis of SLE.

#### **26. CpG-DNA methylation**

B and T cells from patients with SLE exhibit a global decrease in CpG-DNA methylation that correlates with disease activity. Increased methylation of the IL2 gene results in the failure of T cells in patients with SLE to express IL2, while other cytokine genes are overexpressed in T cells in patients with SLE as a result of CpG-DNA hypomethylation. Such genes include IL4, IL6, IL10, IL13, IL17 and genes encoding various surface molecules, namely CD6, CD11a, CD40L and CD70. All these events produce increased numbers of effector memory CD4+ and contribute to the proinflammatory phenotype of SLE.

#### **27. Post-translational histone modifications**

The most common histone modifications include acetylation, phosphorylation, methylation, ubiquitylation and citrullination of histone tails; however, histone modifications are even more complex than CpG-DNA methylation patterns and remain poorly understood. Histone modifications care altered in T cells from patients with SLE. These modifications result in increased TNF expression and subsequent monocyte maturation and cytokine expression. IL2 levels increase while IL17 levels augment as a result of the different expression of the relevant genes.
